Diabetes affects millions of people worldwide and is considered one of the main threats to human health in the 21st century. In 2006, the World Health Organization (WHO) estimated that over 180 million people worldwide had diabetes, and the number is projected to double by 2030. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys and nerves. According to the WHO, approximately 1.1 million people died from diabetes in 2005, and it is estimated that diabetes-related deaths will increase by more than 50% in the next decade. Globally, the socioeconomic burden of diabetes is substantial.
There are two main types of diabetes, designated type 1 and type 2, with type 2 diabetes accounting for over 90% of all diabetes cases globally. Type 1 diabetes is characterized by insulin deficiency, primarily caused by autoimmune-mediated destruction of pancreatic islet β-cells, and type 2 diabetes is characterized by abnormal insulin secretion and concomitant insulin resistance. To prevent the development of ketoacidosis, people with type 1 diabetes must take exogenous insulin for survival. Although those with type 2 diabetes are not dependent on exogenous insulin as much as subjects with type 1 diabetes, they may require exogenous insulin to control blood glucose levels.
As diabetes has become a global health concern, research interest in the condition has rapidly increased. In addition to studies on prevention, many studies with the aim of developing new interventions for the treatment of diabetes, especially type 2 diabetes, have been conducted. Currently available medications for the treatment and management of type 2 diabetes include metformin, sulfonylureas, thiazolidinediones and insulin. However, these therapies are commonly associated with secondary failure and may cause hypoglycemia. Insulin resistance and progressively worsening hyperglycemia caused by reduced β-cell function are major challenges in managing type 2 diabetes. Evidence suggests that patients with insulin resistance do not develop hyperglycemia until their β-cells are unable to produce enough insulin. New agents that can enhance insulin secretion from islet β-cells in a sustained glucose-dependent manner could therefore hold promise for the treatment of type 2 diabetes.
One promising approach is based on inhibition of the serine protease dipeptidyl-peptidase IV (DPP IV), a postproline dipeptidyl aminopeptidase that belongs to the S9b peptidase family of proteolytic enzymes. It is known that DPP IV plays a key role in maintaining glucose homeostasis by controlling the incretin activity of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide). Inhibition of DPP IV is therefore recognized as a novel therapeutic approach for the treatment of type 2 diabetes.
Recently, a series of DPP IV inhibitors were developed. Among these highly potent compounds, alogliptin benzoate (SYR-322) and its analogs demonstrated encouraging antidiabetic efficacy (EP 1586571 (WO 2005/095381); WO 2008/067465; WO 2007/035379, and US 2004/097510).
Alogliptin benzoate can be prepared as described in EP 1586571 (WO 2005/095381) according to the process set forth in Scheme 1:

In accordance with this process, 6-Chlorouracil (1) is alkylated with 2-(bromomethyl)benzonitrile in the presence of NaH and LiBr in a mixture of DMF-DMSO to produce the N-benzyluracil derivative (2) in 54% yield. Compound (2) is further alkylated with iodomethane and NaH in DMF/THF to give the 1,3 disubstituted uracil (3) in 72% yield. Subsequent displacement of chlorouracil (IV) with 3(R)-aminopiperidine dihydrochloride in the presence of either NaHCO3 in hot methanol or K2CO3 in aqueous isopropanol provides alogliptin (4), which is isolated as the corresponding benzoate salt by treatment with benzoic acid in ethanol. The overall yield of this three-stage process is ˜20-25%. One of the disadvantages of above described process is the difficulty to separate and purify mixtures of solvents with high boiling point (for example, DMF/DMSO) for recycling. Another disadvantage is the usage of hazardous materials such as sodium hydride, which requires anhydrous solvents as a reaction media.
Intermediate 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (3) is alternatively obtained by alkylation of 6-chloro-3 methyluracil with 2-(bromomethyl)benzonitrile by means of diisopropylethylamine in hot NMP (WO 2007/035629). Although this process is more technological than the previously described process (EP 1586571), the overall yield is still moderate (50-55%). The problem of mixed solvents (toluene, NMP, diisopropylethylamine) separation persists for this process as well.
Consequently, there is a long-felt need for a process for the preparation of alogliptin and related derivatives which not only overcomes the problems in the art processes as mentioned above, but is also safe, cost effective, and industrially feasible.